The present invention is useful for any active pharmaceutical ingredient (API), which may be administered with a chewing gum. A preferred API is nicotine. The following background mainly concerns nicotine as the API.
Tobacco dependence and reduction thereof is an important field. In recent years, with the recognition of the harmful effects of tobacco smoking, there have been numerous campaigns and programs by governmental agencies and various health groups and other interested organisations to disseminate information about the adverse health effects resulting from tobacco smoking. Moreover, and as a result of this recognition of the harmful effects, there have been many programs directed to attempts in reducing smoking incidence.
Nicotine is an organic compound and is the principal alkaloid of tobacco. Nicotine is the chief addictive ingredient in the tobacco used in cigarettes, cigars, snuff and the like. Nicotine is also an addictive drug, though, and smokers characteristically display a strong tendency to relapse after having successfully stopped smoking for a time. Nicotine is the worlds second most used drug, after caffeine from coffee and tea.
The main problem with tobacco smoking is its enormous implications on health. It is estimated that smoking related diseases cause some 3-4 million deaths per year. According to Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 1995, MMWR 1997; 46:1217-1220, around 500,000 persons in the USA die each year as a result of tobacco use. In fact, excessive smoking is now recognised as one of the major health problems throughout the world. This grim consequence of tobacco smoking has urged many medical associations and health authorities to take very strong actions against the use of tobacco.
Even though tobacco smoking is decreasing in many developed countries today it is hard to see how the societies could get rid of the world's second most used drug.
The most advantageous thing a heavy smoker can do is to reduce or preferably even stop smoking completely. Experience shows, however, that most smokers find this extremely difficult since, mostly, tobacco smoking results in a dependence disorder or craving. The WHO has in its International Classification of Disorders a diagnosis called Tobacco Dependence. Others like the American Psychiatric Association call the addiction Nicotine Dependence. It is generally accepted that these difficulties to stop smoking result from the fact those heavy smokers are dependent on nicotine. The most important risk factors are, however, substances that are formed during the combustion of tobacco, such as carbon monoxide, tar products, aldehydes, and hydrocyanic acid.
The effects of nicotine must be considered. The administration of nicotine can give satisfaction and the usual method is by smoking, either by smoking e.g. a cigarette, a cigar or a pipe. However, smoking has health hazards and it is therefore desirable to formulate an alternative way of administering nicotine in a pleasurable manner that can be used to facilitate withdrawal from smoking and/or used as a replacement for smoking.
When smoking a cigarette, nicotine is quickly absorbed into the smoker's blood and reaches the brain within around ten seconds after inhalation. The quick uptake of nicotine gives the consumer a rapid satisfaction or kick. The satisfaction, then, lasts during the smoking time of the cigarette and for a period of time thereafter. The poisonous, toxic, carcinogenic, and addictive nature of smoking has provided efforts for methods, compositions and devices, which help in breaking the habit of smoking cigarettes.
Nicotine is an addictive poisonous alkaloid C5H4C4H7NCH3, derived from the tobacco plant. Nicotine is also used as an insecticide. Approximately 40 milligrams of nicotine is able to kill an adult (Merck Index).
Nicotine replacement products are important in the reduction of smoking. One way to reduce smoking is to provide nicotine in a form or manner other than by smoking and some products have been developed to fulfill this need. Nicotine containing formulations are currently the dominating treatments for tobacco dependence.
The successes in achieving reduction in the incidence of smoking have been relatively poor using presently known products. The present state of the art involves both behavioral approaches and pharmacological approaches. More than 80% of the tobacco smokers who initially quit smoking after using some behavioral or pharmacological ap proach. These persons who singly reduce smoking incidence generally relapse and return to the habit of smoking at their former rate of smoking within about a one year's period of time.
As an aid for those who are willing to stop smoking there are several ways and forms of nicotine replacement products available on the market; such as nicotine chewing gum. Several methods and means have been described for diminishing the desire of a subject to use tobacco, which comprises the step of administering to the subject nicotine or a derivative thereof as described in e.g., U.S. Pat. No. 5,810,018 (oral nicotine spray), U.S. Pat. No. 5,939,100 (nicotine containing microspheres) and U.S. Pat. No. 4,967,773 (nicotine containing lozenge).
Nicotine-containing nose drops have been reported (Russell et al., British Medical Journal, Vol. 286, p. 683 (1983); Jarvis et al., Brit. J. of Addiction, Vol. 82, p. 983 (1987)). Nose drops, however, are difficult to administer and are not convenient for use at work or in other public situations. Ways of administrating nicotine by way of delivering nicotine directly into the nasal cavity by spraying is known from U.S. Pat. No. 4,579,858; DE 32 41 437; and WO 93/127 64. There may, however, be local nasal irritation with use of nasal nicotine formulations. The difficulty in administration also results in unpredictability of the dose of nicotine administered.
The use of skin patches for transdermal administration of nicotine has been reported (Rose, in Pharmacologic Treatment of Tobacco Dependence, (1986) pp. 158-166, Harvard Univ. Press). Nicotine-containing skin patches that are in wide use today can cause local irritation and the absorption of nicotine is slow and affected by cutaneous blood flow.
Also, inhaling devices resembling a cigarette are known for uptake of nicotine vapours as suggested in U.S. Pat. No. 5,167,242. Said means and methods address the problems associated with addiction to nicotine.
Nicotine chewing gum is an important approach. One of the most successful approaches to date in reducing the incidence of smoking relies upon nicotine containing chewing gum that is designed to reduce smoking withdrawal symptoms. The reported success rate is approximately twice that of placebo.
Various approaches have been discussed for smoking reduction and/or cessation. One successful product that is used as a smoking substitute and/or as a smoking cessation aid and which is based on nicotine is the chewing gum Nicorette®. This product was one of the first nicotine replacement forms that was approved by the Food and Drug Administration (FDA) and is still one of the most used nicotine replacement products. Nicorette® chewing gum has been on the market in many countries for several years. In this chewing gum the nicotine is present in the form of a complex with an insoluble cation-exchanger (polacrilex) that is dispersed in a gum base. The nicotine is slowly released from the gum due to chewing and will reach similar plasma levels as when smoking a cigarette after about 30 minutes depending on the chewing technique, i.e., slow or active. Patents related to this product are, e.g., U.S. Pat. Nos. 3,877,468; 3,901,248; and 3,845,217.
WO 98/23165 discloses a chewing gum wherein nicotine may be in the coating. This concept may provide rapid release of the nicotine from the coated chewing gum, but not a sufficiently rapid buccal uptake of the nicotine. The fraction of the released nicotine that is not immediately absorbed will be flushed down in the gastrointestinal (G.I.) tract by the saliva, thereby possibly causing hiccups and other G.I. side effects. Once absorbed by the G.I. route, this swallowed nicotine will be subjected to first pass metabolism.
WO 00/13662 discloses a chewing gum for systemic, oral administration of an active whereby said active is administered by the chewing gum composition in a bi-phasic manner. The bi-phasic delivery is obtained by the gum matrix as such, not from any coating.
WO 00/19977 discloses a substantially moisture-free and possibly coated chewing gum for delivery of an active. The possible coating is not described as being buffered.
U.S. Pat. No. 5,433,960, assigned to William Wrigley Jr. Company, discloses a stick-shaped chewing gum being coated with an edible film, which comprises at least one active chewing gum agent such as sweetener, flavor, softener, slip agent, flavor enhancer, antioxidant and/or color. The coating may comprise a first layer as an edible film and a second layer comprising e.g. wax, fat, oil and/or a lipid derivative. It is not disclosed that the stick-shaped chewing gum with its coating may comprise any other drug than said active chewing gum agent.
WO 02/102357, assigned to Pharmacia AB, discloses a nicotine-containing chewing gum product comprising at least one coating, which coating is buffered.
U.S. Pat. No. 5,135,761, assigned to the Wrigley Company, discloses a coated chewing gum comprising a center, an emulsifier coating covering the center, and a hard panned coating covering the emulsifier coating. The emulsifier coating does not contain a polymer.
EP 302024A, assigned to Warner-Lambert, discloses a chewing gum comprising a first portion containing an L-aspartic acid derived sweetener, a second portion containing at least one flavoring agent, and a protective barrier film between the first and the second portions.
U.S. Pat. No. 4,828,845, assigned to Warner-Lambert, discloses a process for producing a coated chewing gum, whereby at least three coating solutions are applied one after the other by spraying on to a chewing gum core.
ZA 8702849, assigned to Warner-Lambert, discloses a chewing gum with a core and at least two coating solutions, both solutions comprising sorbitol and film-forming agents, such as hydroxypropylmethyl cellulose (“HPMC”).
U.S. Pat. No. 4,933,190, assigned to Warner-Lambert, discloses a chewing gum capable of releasing increased amounts of sweetness, which has a first inner coating comprising polyvinyl acetate and a second outer coating comprising a hydrophilic polymer.
None of the above references disclose any solution to the combined problems of obtaining a long lasting effect of flavoring agent(s), domination of flavoring agents in the coating(s) over flavoring agent(s) in the core, avoiding problems of chemical or pharmaceutical incompatibility between a drug in the core and flavoring agent(s) in the coating(s), and/or increasing the control of the release of the drug.